CN105456201B - The preparation method of ambroxol salbutamol pellet - Google Patents
The preparation method of ambroxol salbutamol pellet Download PDFInfo
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- CN105456201B CN105456201B CN201510902120.5A CN201510902120A CN105456201B CN 105456201 B CN105456201 B CN 105456201B CN 201510902120 A CN201510902120 A CN 201510902120A CN 105456201 B CN105456201 B CN 105456201B
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- pellet
- salbutamol
- ambroxol
- preparation
- starch
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Abstract
The present invention relates to ambroxol salbutamol pellets, belong to field of pharmaceutical preparations.PLURONICS F87, meglumine and the mannitol that the pellet of the present invention appropriately adds in, the stability and bioavilability of ambroxol hydrochloride and salbutamol sulfate in preparation can be significantly improved, stable quality, significant effect can effectively treat the respiratory diseases such as acute/chronic bronchitis and asthma.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of ambroxol salbutamol pellet and preparation method thereof.
Background technology
Respiratory disease is a kind of common disease, frequently-occurring disease, and major lesions are in trachea-bronchial epithelial cell, lung and thoracic cavity, lesion
The lighter's mostly cough, pectoralgia, breathing is impacted, severe one is had difficulty in breathing, anoxic or even respiratory failure and it is lethal.Death in city
Rate accounts for the 3rd, and in rural area then account for the first.Should more pay attention to, due to atmosphere pollution, smoking, aging of population and other because
Element makes chronic obstructive pulmonary disease both domestic and external (abbreviation chronic obstructive pulmonary disease, including chronic bronchitis, pulmonary emphysema, pulmonary heart disease), bronchus
The incidence of the diseases such as asthma, lung cancer, lung's dispersivity interstitial fibrosis and pulmonary infection, the death rate are growing on and on.
According to national urbans in 2006 and the statistical number of the rural area top ten principal disease cause of death, respiratory system disease
Sick (not including lung cancer) accounts for the 4th (13.1%) in the Death causes in city, is accounted in rural area the 3rd (16.4%).Due to
Physical and chemical factor, biotic factor inhale the factors such as people and population ages aging caused by atmosphere pollution, smoking, Industrial Economic Development,
Make the incidence of respiratory disease such as lung cancer, bronchial asthma in recent years substantially increase, Chronic Obstructive Pulmonary Disease occupies height not
Under (more than 8% in 40 years old or more crowd).Though pulmonary tuberculosis rate is controlled, have again in recent years and increase trend.Lung thrombus bolt
Plug disease has constituted important health care problem, and pulmonary hypertension is also of increasing concern in recent years.Between pulmonary Diffuse
The disease incidences such as matter fibrosis and immunocompromised pulmonary infection are increased.The major causes of death of AIDS is felt for lung
Dye, particularly pneumocystis carinii pneumonia.Since the end of the year 2002, the infectiousness atypia lung that is broken out in China and world wide
Scorching (serious acute respiratory syndrome, SARS) epidemic situation, due to mostly occurring in the young and the middle aged, infectiousness is strong, and case fatality rate is high, and lacks
Targetedly drug, thus the fear of the masses is caused, while bring about great losses to national economy.Go out at present in multiple countries
Existing human avian influenza case fatality rate is more than 60%.And it is also lung that avian influenza virus, which invades main target organ in human body,.This positive explanation is exhaled
Desorption system disease is still very big to health of our people harm, prevents arduous task.
Ambroxol hydrochloride (Ambroxol Hydrochloride) is also known as ambroxol hydrochloride, the entitled trans -4- of chemistry
[(2- amino 3,5- dibromo-benzyls) amino] cyclohexanol hydrochloridumi, it be expectorant bromhexine active metabolite (N- demethyls,
Cyclohexyl contraposition introduces trans hydroxyl), toxicity is less than bromhexine, and activity is higher than bromhexine.Ambroxol hydrochloride is by German vigorous
Lin Geyinge writing brushes company research and development mucolytic, the medicine in early 1980s first Germany list, then France,
The successive listing of many countries such as Italy, Japan, Spain is the glutinous phlegm lytic agent of a new generation, can improve expectoration, and with rush
Into pulmonary surfactant and Airway secretion and the effect of ciliary movement.Ambroxol hydrochloride can clinically adjust mucus with sticking
Slurry secretion, activates fibre swing, is easy to dilute sputum, strengthens mucus and outwards transports, is easy to discharge, it can also promote lung surface
Active material synthesizes, and to maintain alveolar tension, ensures lung functions index;Promote antibiotic to tissue infiltration, to improve concentration,
Enhance bactericidal effect;It is anti-oxidant, inflammatory mediator release is reduced, with the reaction that reduces inflammation;It is cooperateed with bronchus spasmolysis substance, to carry
The effect of high spasmolysis drug.Therefore, which clinically can be widely applied to the acute and chronic breathing with respiratory tract abnormal secretion
The auxiliary treatment of the eliminating the phlegm treatment of road illness, particularly chronic bronchitis, transient respiratory distress of the newborn disease and pulmonary surgery, tool
It is toxic it is low, it is curative for effect and can with antibiotic and with generate good synergy the advantages that, be most common expectorant it
One.In recent years in the emphasis hospital administration ranking of China main cities, it ranks forefront always.
Salbutamol sulfate (Salbutamol Sulfate) also known as albuterol, main component are salbutamols, chemistry
Entitled 1- (4- hydroxyl -3- hydroxymethyl phenyls) -2- (tert-butylamine base) ethyl alcohol, is a kind of highly selective exciting bronchial smooth muscle
β-adrenoreceptor excitant, bronchial smooth muscle is made to relax, so as to release bronchial muscular spasm.To bronchiectasis
Effect is stronger, and weaker to the β1-receptor effect of heart, is current safer, most common antiasthmatic.Suitable for preventing branch gas
The bronchial spasm of pipe asthma, asthmatic bronchitis and emphysematic patients, alleviate because bronchial asthma, chronic bronchitis and
Symptoms, the advantage such as expiratory dyspnea are rapid-action caused by the airway obstructive diseases such as pulmonary emphysema, can improve patient symptom rapidly,
Spasmolysis is relievingd asthma, eliminating the phlegm, and shortcoming is to act on persistently, not functioning only as the effect for alleviating patient's asthma symptoms;Long period application can
Beta-receptor is caused to adjust downwards, patient is made to occur losing beta receptor agonist quick or even invalid to treating asthma drug resistance phenomenon.
The dosage forms such as solution and granule containing ambroxol hydrochloride and salbutamol sulfate are had existed in the prior art,
But have no the report of pellet.
In addition, salbutamol sulfate and ambroxol hydrochloride are active ingredient in same minimum preparation unit, it is long-term to protect
When depositing, chemical compatible change occurs due to possible between each ingredient, easily generates by-product, therefore meeting reducing effect or increase pair are made
With product stability is not ideal enough.
The content of the invention
In view of the synergistic effect of ambroxol hydrochloride and salbutamol sulfate, the purpose of the present invention is to provide a kind of safety
Effectively, stable quality, patient adaptability is strong, significant effect, can effectively treat the respiratory systems such as acute/chronic bronchitis and asthma
The ambroxol salbutamol pellet of disease.
Under study for action, it has been surprisingly found that, the PLURONICS F87 that is appropriately added in the preparation of preparation, meglumine and
Mannitol can significantly improve the stability and bioavilability of ambroxol hydrochloride and salbutamol sulfate in preparation, for medicine
The Clinical practice of product is of great significance.
The present invention solve the technical problem technical solution be:
A kind of ambroxol salbutamol pellet, is made of the component of following weight:
Salbutamol sulfate:8-10g;
Ambroxol hydrochloride:15-20g;
PLURONICS F87:8-10g;
Meglumine:6-8g;
Mannitol:2-4g;
Filler:200-400g;
Disintegrant:10-20g;
Adhesive:In right amount.
Optimizing prescriptions are:
Salbutamol sulfate:10g;
Ambroxol hydrochloride:20g;
PLURONICS F87:8g;
Meglumine:8g;
Mannitol:4g;
Filler:400g;
Disintegrant:20g;
Adhesive:In right amount.
The filler is selected from one or more of starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.
The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked carboxymethyl
One or more of sodium cellulosate and sodium alginate.
The adhesive in starch, pregelatinized starch, hydroxypropylcellulose, hydroxypropyl methylcellulose and povidone one
Kind is several.
Its preparation method is:
1) supplementary material of recipe quantity is weighed, it is spare to cross 80-120 mesh sieves respectively;
2) adhesive after sieving is taken to add in distilled water, binder solution is made;
3) by salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, the filler after sieving
It is uniformly mixed with disintegrant by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 20-40min at 50-70 DEG C, sieve, pack to obtain the final product.
To obtain the final product.
Preferably preparation method is:
1) supplementary material of recipe quantity is weighed, it is spare to cross 100 mesh sieves respectively;
2) adhesive after sieving is taken to add in distilled water, binder solution is made;
3) by salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, the filler after sieving
It is uniformly mixed with disintegrant by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 30min at 60 DEG C, sieve, pack to obtain the final product.
Active component content the beneficial effects of the invention are as follows the ambroxol salbutamol pellet dramatically increases;Stability
It greatly improves;Therefore stable quality, significant effect can effectively treat the respiratory diseases such as acute/chronic bronchitis and asthma.
Specific embodiment
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.
Unless otherwise defined, all professional and scientific terms used in text and meaning known to one skilled in the art
Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the method for the present invention.Wen Zhong
The preferred implement methods and materials are for illustrative purposes only.
Embodiment 1
Prescription:
Salbutamol sulfate:8g;
Ambroxol hydrochloride:15g;
PLURONICS F87:8g;
Meglumine:8g;
Mannitol:4g;
Lactose:400g;
Sodium carboxymethyl starch:20g;
Hydroxypropyl methylcellulose:In right amount.
Preparation method is:
1) supplementary material of recipe quantity is weighed, it is spare to cross 100 mesh sieves respectively;
2) hydroxypropyl methylcellulose after sieving is taken to add in distilled water, binder solution is made;
3) by after sieving salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, lactose and
Sodium carboxymethyl starch is uniformly mixed by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 30min at 60 DEG C, sieve, pack to obtain the final product.
Embodiment 2
Prescription:
Salbutamol sulfate:10g;
Ambroxol hydrochloride:20g;
PLURONICS F87:8g;
Meglumine:6g;
Mannitol:2g;
Lactose:300g;
Low-substituted hydroxypropyl cellulose:10g;
Hydroxypropylcellulose:In right amount.
Preparation method:
1) supplementary material of recipe quantity is weighed, it is spare to cross 80 mesh sieves respectively;
2) hydroxypropylcellulose after sieving is taken to add in distilled water, binder solution is made;
3) by after sieving salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, lactose and
Low-substituted hydroxypropyl cellulose is uniformly mixed by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 30min at 50 DEG C, sieve, pack to obtain the final product.
Embodiment 3
Prescription:
Salbutamol sulfate:8g;
Ambroxol hydrochloride:18g;
PLURONICS F87:10g;
Meglumine:6g;
Mannitol:4g;
Starch:400g;
Microcrystalline cellulose:15g;
Povidone:In right amount.
Preparation method:
1) supplementary material of recipe quantity is weighed, it is spare to cross 80 mesh sieves respectively;
2) povidone after sieving is taken to add in distilled water, binder solution is made;
3) by after sieving salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, starch and
Microcrystalline cellulose is uniformly mixed by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 30min at 50 DEG C, sieve, pack to obtain the final product.
4 stability test of embodiment
Comparative example 1 is identical with embodiment using preparation method;Prescription is as follows:
Salbutamol sulfate:8g;
Ambroxol hydrochloride:15g;
Lactose:400g;
Sodium carboxymethyl starch:20g;
Hydroxypropyl methylcellulose:In right amount.
Comparative example 2 is identical with embodiment using preparation method;Prescription is as follows:
Salbutamol sulfate:8g;
Ambroxol hydrochloride:15g;
PLURONICS F87:8g;
Lactose:400g;
Sodium carboxymethyl starch:20g;
Hydroxypropyl methylcellulose:In right amount.
1. accelerated stability test
Embodiment 1, comparative example 1 and 2 gained ambroxol salbutamol pellet of comparative example are put into intensity of illumination 4500lx respectively
Under the conditions of 10 days, sampled respectively at the 0th, 5,10 day, every quality index such as detection level, related substance the results are shown in Table 1.
1 ambroxol salbutamol pellet influence factor result of the test of table
The result shows that:Ambroxol salbutamol pellet prepared by the present invention each component content under intense light conditions becomes without apparent
Change, stability is significantly better than comparative example.To find out its cause, it is because the ordinary adjuvants in comparative example can not be preferably to active ingredient
Support and stabilization are played, and then causes chemical compatible change may occur between each ingredient, easily generates by-product;And by
It is more than general state of the art in the content of active ingredient, stability is caused more to substantially reduce.
2. accelerated test
By 1 gained ambroxol salbutamol pellet of embodiment be placed in 40 DEG C, the constant temperature of RH20%, 6 months in constant humidity cabinet, point
It was not sampled in the 0th, 1,2,3,6 month, measures every quality index such as content, related substance, the results are shown in Table 2.
2 ambroxol salbutamol pellet accelerated test result of table
The result shows that:Ambroxol salbutamol pellet is placed 6 months under conditions of 40 DEG C, RH20%, is compared with 0 month
Compared in addition to related substance is increased slightly, other every quality index have no significant change, and stable quality is reliable, meets regulation.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention
It encloses, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete
Entity or method, if with the right of application defined in it is identical, also or a kind of equivalent change, will
It is considered as being covered by among the right.
Claims (1)
1. a kind of preparation method of ambroxol salbutamol pellet, is made of the component of following weight:
Salbutamol sulfate:8-10g;
Ambroxol hydrochloride:15-20g;
PLURONICS F87:8-10g;
Meglumine:6-8g;
Mannitol:2-4g;
Filler:200-400g;
Disintegrant:10-20g;
Adhesive:In right amount
Preparation method is:
1) supplementary material of recipe quantity is weighed, it is spare to cross 80-120 mesh sieves respectively;
2) adhesive after sieving is taken to add in distilled water, binder solution is made;
3) by after sieving salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol, filler and collapse
Solution agent is uniformly mixed by equal increments method, adds in above-mentioned binder solution and softwood is made;
4) pellet is prepared into using extrusion spheronization technology, dries 20-40min at 50-70 DEG C, sieve, pack to obtain the final product;
The filler is selected from one or more of starch, lactose, dextrin and Icing Sugar;
The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked carboxymethyl fiber
One or more of plain sodium and sodium alginate;
One kind in starch, pregelatinized starch, hydroxypropylcellulose, hydroxypropyl methylcellulose and povidone of the adhesive or
It is several.
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CN101416956A (en) * | 2007-10-22 | 2009-04-29 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride injection |
CN101502494A (en) * | 2009-04-01 | 2009-08-12 | 王保明 | Bromhexine hydrochloride freeze-dried injection and preparation method thereof |
CN104622854A (en) * | 2014-12-22 | 2015-05-20 | 青岛正大海尔制药有限公司 | Tablet containing ambroxol hydrochloride and salbutamol sulfate |
Family Cites Families (1)
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RU2012138909A (en) * | 2010-03-31 | 2014-05-10 | Гленмарк Фармасьютикалс Лимитед | PHARMACEUTICAL POWDER COMPOSITION FOR INHALATIONS |
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CN101416956A (en) * | 2007-10-22 | 2009-04-29 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride injection |
CN101502494A (en) * | 2009-04-01 | 2009-08-12 | 王保明 | Bromhexine hydrochloride freeze-dried injection and preparation method thereof |
CN104622854A (en) * | 2014-12-22 | 2015-05-20 | 青岛正大海尔制药有限公司 | Tablet containing ambroxol hydrochloride and salbutamol sulfate |
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Address after: 266000 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee after: Zhengda Pharmaceutical (Qingdao) Co., Ltd. Address before: 266000 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee before: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. |